ABSTRACT
The ability of organoselenium molecules to mimic the activity of the antioxidant selenoenzyme glutathione peroxidase (GPx) allows for their use as antioxidant or prooxidant modulators in several diseases associated with the disruption of the cell redox homeostasis. Current drug design in the field is partially based on specific modifications of the known Se-therapeutics aimed at achieving more selective bioactivity towards particular drug targets, accompanied by low toxicity as the therapeutic window for organoselenium compounds tends to be very narrow. Herein, we present a new group of Se-based antioxidants, structurally derived from the well-known group of GPx mimics-benzisoselenazol-3(2H)-ones. A series of N-substituted unsymmetrical phenylselenides with an o-amido function has been obtained by a newly developed procedure: a copper-catalyzed nucleophilic substitution by a Se-reagent formed in situ from diphenyl diselenide and sodium borohydride. All derivatives were tested as antioxidants and anticancer agents towards breast (MCF-7) and leukemia (HL-60) cancer cell lines. The highest H2O2-scavenging potential was observed for N-(3-methylbutyl)-2-(phenylselanyl)benzamide. The best antiproliferative activity was found for (-)-N-(1S,2R,4R)-menthyl-2-(phenylselanyl)benzamide (HL-60) and ((-)-N-(1S,2R,3S,6R)-(2-caranyl))benzamide (MCF-7). The structure-activity correlations, including the differences in reactivity of the obtained phenyl selenides and corresponding benzisoselenazol-3(2H)-ones, were performed.
Subject(s)
Antioxidants/chemical synthesis , Hydrogen Peroxide/metabolism , Neoplasms/metabolism , Organoselenium Compounds/chemical synthesis , Antioxidants/chemistry , Antioxidants/pharmacology , Cell Proliferation/drug effects , HL-60 Cells , Humans , MCF-7 Cells , Molecular Structure , Neoplasms/drug therapy , Organoselenium Compounds/chemistry , Organoselenium Compounds/pharmacology , Structure-Activity RelationshipABSTRACT
Organoselenium compounds are well-known glutathione peroxidase (GPx) mimetics that possess antioxidants/prooxidant properties and are able to modulate the concentration of reactive oxygen species (ROS), preventing oxidative stress in normal cells or inducing ROS formation in cancer cells leading to apoptosis. The purpose of this study was the synthesis of potent GPx mimics with antioxidant and anticancer activity along with improved bioavailability, as a result of good solubility in protic solvents. As a result of our research, glutathione peroxidase (GPx) mimetics in the form of water-soluble benzeneseleninic acid salts were obtained. The procedure was based on the synthesis of 2-(N-alkylcarboxyamido)benzeneselenenic acids, through the oxidation of benzisoselenazol-3(2H)-ones or analogous arenediselenides with an amido group, which were further converted to corresponding potassium salts by the treatment with potassium tert-butanolate. All derivatives were tested as potential antioxidants and anticancer agents. The areneseleninic acid salts were significantly better peroxide scavengers than analogous acids and the well-known organoselenium antioxidant ebselen. The highest activity was observed for the 2-(N-ethylcarboxyamido)benzeneselenenic acid potassium salt. The strongest cytotoxic effect against breast cancer (MCF-7) and human promyelocytic leukemia (HL-60) cell lines was found for 2-(N-cyclohexylcarboxyamido)benzeneselenenic acid potassium salt and the 2-(N-ethylcarboxyamido)benzeneselenenic acid, respectively. The structure-activity correlations, including the differences in reactivity of benzeneseleninic acids and corresponding salts were evaluated.
ABSTRACT
A series of new chiral benzisoselenazol-3(2H)-ones substituted on the nitrogen atom with three monoterpene moieties-p-menthane, pinane and carane-was synthesized. The compounds were obtained by the reaction of 2-(chloroseleno)benzoyl chloride with an appropriate terpene amine, first synthesized by a multistep methodology starting from the corresponding alcohol (p-menthane system) or alkene (pinene and carene systems). Compounds were tested as antioxidants and anticancer agents. The N-isopinocampheyl-1,2-benzisoselenazol-3(2H)-one was the best peroxide scavenger and antiproliferative agent on the human promyelocytic leukemia cell line HL-60. The N-menthyl-1,2-benzisoselenazol-3(2H)-one revealed the highest anticancer potential towards breast cancer line MCF-7. The influence of structure and chirality on the bio-activity of the obtained organoselenium compounds was thoroughly evaluated.
ABSTRACT
The twisted structure of ditellurides, in a similar way as in other dichalcogenes, leads to different absorption of circularly polarized light by quasi-enantiomeric chiral orbitals. Chiral optically active ditellurides are not common compounds and this phenomenon is not widely reported. As chiral ditellurides found an application in asymmetric synthesis, their molecular structure, understood as their conformation, became an important factor for understanding their reactivity. Until now there are few examples of chiral ditellurides known and their structure was not analyzed in details. This article presents the results of our most recent research on the structure of chiral ditellurides investigated by electronic circular spectroscopy (ECD) supported by quantum-chemical calculation. This enables us to suggest a relationship between chirality of alkyl substituent and chirality (conformation) of ditelluride.
Subject(s)
Organometallic Compounds/chemistry , Quantum Theory , Tellurium/chemistry , Alkylation , Circular Dichroism , Models, Molecular , Molecular Conformation , StereoisomerismABSTRACT
New chiral camphane-derived benzisoselenazol-3(2H)-ones and corresponding diselenides have been synthetized using a convenient one-pot procedure. Se-N bond was efficiently converted to an Se-Se bond, which could also be easily re-oxidized to the initial benzisoselenazolone moiety. The antioxidant activity of camphor derivatives was evaluated and compared to the reactivity of a series of N-amino acid benzisoselenazol-3(2H)-ones obtained by a modified procedure involving the improved synthesis and isolation of the diseleno bis(dibenzoic) acid. The most efficient peroxide scavengers, N-bornyl and N-leucine methyl ester benzisoselenazol-3(2H)-ones, were further evaluated as cytotoxic agents on four cancer cell lines (MCF-7, HEP G2, HL 6, and DU 145) and normal cell line PNT1A. The highest antiproliferative potential was evaluated for two compounds bearing a 3-methylbutyl carbon chain, N-leucine methyl ester and N-3-methylbutyl benzisoselenazol-3(2H)-ones.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antioxidants/chemical synthesis , Organoselenium Compounds/chemical synthesis , Thiazoles/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Antioxidants/chemistry , Antioxidants/pharmacology , Azoles/chemistry , Catalysis , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Isoindoles , MCF-7 Cells , Molecular Structure , Organic Chemicals , Organoselenium Compounds/chemistry , Organoselenium Compounds/pharmacology , Thiazoles/chemistry , Thiazoles/pharmacologyABSTRACT
A series of N-alkyl benzisoselenazol-3(2H)-ones has been obtained and transformed to corresponding diselenides by the reduction with sodium borohydride. Additionally, efficient methodology for the oxidative Se-N bond formation by potassium iodate has been presented, new conversion of diselenide to benzisoselenazolone was observed. The GPx-like activity of all synthetized derivatives has been evaluated by NMR. N-Allyl diselenide was up to five times better antioxidant than ebselen. Anticancer capacity towards MCF7 and DU145 cancer cells has been also tested. The highest antiproliferative activity was obtained for N-cyclohexyl benzisoselenazolone.
